PROJECT SUMMARY/ABSTRACT Large-scale genetic studies have made tremendous progress identifying the heritable basis for many neurodevelopmental, psychiatric disorders. However, connecting common genotypes to phenotypes -- and their underlying biological mechanisms -- in the nervous system is often complicated by complex patterns of linkage disequilibrium (LD) as well as the long-range action of genomic regulation. Common genetic variation within the 17q21.31 locus shows strong, highly pleiotropic genome-wide associations with several brain-related phenotypes including neuroticism, PTSD, brain volume, educational attainment, as well as multiple neurodegenerative disorders, among others. This locus, however, is among the most complex in the human genome, as it is known to harbor at least 8 common, complex structural haplotypes, including a ~900 kb inversion (?H2?) under positive selection and present in ~20% of Europeans. Consequently, the specific haplotypes mediating these brain relevant trait-associations -- and the biological mechanisms through which this risk is conferred -- remain unknown. This proposal leverages recently developed 17q21.31 haplotype-specific SNP imputation panels to fully elucidate the ?phenome-wide? impact of these common structural haplotypes on a wide range of neurodevelopmental, psychiatric, cognitive, and neuroimaging phenotypes. In Aim 1, we interrogate haplotype-specific neurodevelopmental trajectories in the iPSYCH case-cohort, comprising ~90k Danish individuals with clinical and psychiatric diagnoses from nationwide medical registers. In Aim 2, we characterize haplotype-specific associations with neuroimaging, psychiatric symptom, and cognitive phenotypes among up to ~500k British 40-70 year old volunteers in the UK Biobank and in the ABCD Study, a community sample of ~10k 9-11 year olds in the US. In Aim 3, we interrogate the molecular impact of haplotypes on gene expression and coexpression patterns in human brain across development. Finally, we perform single-cell RNA-seq and ATAC-seq on primary human neural progenitor cell lines ascertained for distinct haplotypes, enabling direct assessment of the allelic impact on developmental cell growth, gene expression, and chromatin accessibility. Altogether, proposed studies will characterize the ?phenome-wide? impact of common 17q21.31 complex structural variation in the population and deconstruct the specific neurobiological mechanisms underlying these broad associations with neurodevelopmental and psychiatric traits.